6 Factors Which Can Affect The Conversion of T4 to T3

For those people who have normal T4 levels, but low or depressed T3 levels, a thyroid hormone conversion problem needs to be suspected. The thyroid gland mostly produces thyroxine, which is also known as T4. The thyroid gland also produces a small amount of triiodothyronine, which is T3. Most of the T3 is produced by the conversion of T4 to T3. But there are numerous factors which can affect the conversion of T4 to T3, which I’ll be discussing in this post.

Before I discuss some of the factors which can affect the conversion of T4 to T3, I’d like to briefly talk about this process. The enzyme 5′ -deiodinase is responsible for this conversion process. There are three forms of this enzyme, which include deodinase type I, deodinase type II, and deodinase type III. The type 1 and type II deiodinases are primarily responsible for the conversion of T4 to T3, whereas the type III deiodinase is mainly involved in the inactivation of T4 and T3 (1)(2). Most of this conversion takes place in the liver, although some of the conversion also takes place in the gastrointestinal tract. As a result, if someone has liver problems and/or gut dysbiosis then this can potentially affect the conversion of T4 to T3. A certain percentage of T4 is also converted into reverse T3, which I have spoken about in a different post entitled “Reverse T3: What You Need To Know About It“.

So why is it a concern if someone has problems converting T4 into T3? Well, T3 is the active form of thyroid hormone. Unfortunately not all endocrinologists test for T3, but when they do they will either test for total T3, where most of T3 is bound to a protein, or free T3, which isn’t bound to a protein. Free T3 is what actually binds to the thyroid receptor. If someone has normal T4 levels but low T3 levels then this is considered to be a hypothyroid condition. Many medical doctors will only test the TSH and T4 levels, and the reason for this is because if the T3 is low then the TSH will typically be elevated, although this isn’t always the case. I always recommend testing both the free T3 and free T4, along with the TSH. If doing an initial thyroid panel it’s also a good idea to test the reverse T3, along with the thyroid antibodies.

Why Do Most Medical Doctors Give Synthetic T4?

When someone presents with hypothyroidism, most medical doctors will recommend a form of levothyroxine, which is synthetic T4. A common brand is Synthroid, although there are other forms as well. But if T3 is what actually binds to the receptor, wouldn’t it make sense to give the person T3 instead? Well, some medical doctors will recommend synthetic T3 in the form of Cytomel. However, many doctors are understandably cautious about doing this, as too high of a dosage can put the person into a hyperthyroid state. Synthetic T4 will convert into T3, but of course if someone has a conversion problem then this won’t be the case. Plus, even if someone doesn’t have a conversion problem they might do better taking a natural form of thyroid hormone such as Armour or Nature-Throid, which consists of both T4 and T3, along with T1, T2, and calcitonin.

Now that you have a better understanding of the importance of T3, I’d like to discuss the five factors which can have a negative effect on the conversion of T4 to T3.

Factor #1: Problems with the liver. Since most of the conversion of T4 to T3 takes place in the liver, it would make sense that some health conditions affecting the liver can decrease the conversion of T4 to T3. However, this isn’t always the case, as one study which investigated the relationships between thyroid function in obese adolescents with non-alcoholic fatty liver showed that they had a higher conversion of T4 to T3 due to increased deiodinase activity as a compensatory mechanism for fat accumulation (3). With that being said, if someone has problems converting T4 to T3 it usually is a good idea to give some liver support, such as milk thistle and N-acetylcysteine.

Factor # 2: Gut dysbiosis. As I mentioned earlier, the good bacteria in the gut helps to convert T4 into T3 through the help of an enzyme called intestinal sulfatase. There isn’t much evidence in the literature showing that gut dysbiosis negatively affects the conversion of T4 to T3, but obviously if someone has dysbiosis then this should be addressed even if they aren’t having a conversion issue. I did come across one study which showed that Crohn’s disease can affect the conversion of T4 to T3 (4).

Factor # 3: Selenium deficiency. The iodothyronine deiodinases all contain selenium in the form of selenocysteine, and they play crucial roles in determining the circulating and intracellular levels of T3 (5). Numerous studies show that a selenium deficiency can affect the conversion of T4 to T3 (6)(7)(8). However, this might only be the case with a severe selenium deficiency, as one study showed that only when selenium levels were decreased by more than 80% was deiodinase activity markedly decreased (5).

Factor # 4: Stress. Elevated cortisol levels can affect the conversion of T4 to T3. Studies show that stress can inhibit both type I iodothyronine 5′-deiodinase activity (9), as well as type II 5′-deiodinase activity (10)(11). This is yet another reason why it’s important to improve your stress handling skills.

Factor # 5: Certain medications. Amiodarone is an anti-arrhythmic compound, and due to the structural similarity between this and thyroid hormone it apparently inhibits the activity of 5′-deiodinase (12). Beta blockers are commonly taken in hyperthyroid conditions, and certain ones such as propranolol, alprenolol, atenolol, and metroprolol can affect the conversion of T4 to T3 (13).

In summary, normal T4 levels along with low T3 levels frequently indicate a conversion problem. This involves the enzyme 5′-deiodinase, and is one reason why when obtaining a thyroid panel you want to not only look at the TSH and free T4 levels, but also the free T3. And it usually is a good idea to look at the reverse T3 as well. Six common factors which affect the conversion of T4 to T3 include problems with the liver, gut dysbiosis, a selenium deficiency, high cortisol levels, certain medications, and pro-inflammatory cytokines.

Comments

2) since milk thistle increases the rate drugs are cleared through the liver, should it be avoided if taking thyroid prescriptions? does the same hold true for NAC?

3) especially for those having MTHFR defects, any valid tests to accurately measure the amount of each of these: deodinase type I, deodinase type II, and deodinase type III? how can one increase deodinase type I and deodinase type II AND/OR decrease Type III?

I don’t think that too much selenium will reduce T4 to T3 conversion, although I’m not 100% certain of this. You do want to be careful about taking high doses of selenium, as it can be toxic. High RT3 can decrease the conversion, but depressed cortisol levels shouldn’t decrease the conversion. I commonly give milk thistle and other herbs/nutrients which increase glutathione (i.e. NAC) to patients who are taking thyroid medication, and it doesn’t seem to decrease the effectiveness. Unfortunately I’m not familiar with any labs which allow you to test the different types of deiodinase enzymes.

My tsh is very low as is my t3 with low to normal t4. Would you suggest i have my doctor test for the above factors (i.e low selenium etc.) Prior to supplementing on my own? Would the above factors still apply when you have very low t3 as well as very low tsh?

Are you taking synthetic thyroid hormone? If so then this can depress the TSH and the thyroid hormone levels can still show up as being low. If you aren’t taking any thyroid hormone medication yet have a low TSH and low thyroid hormone levels then this can be caused by low levels of serotonin or dopamine, or can also be due to elevated cytokines, prolactin, or cortisol.

Low TSH with low thyroid hormones can also be a sign of pituitary problems. You need to research the right Endocrinologist. (Most Endocrinologist are diabetes specialists and have limited knowledge of the pituitary.) I speak from experience. It took me over 20years to get a diagnosis.

Thank you for this article. I was diagnosed with Graves Hyperthyroidism. I have suppressed TSH at less than .01, normal range for T4, and my T3 was elevated. So does that mean I could have a conversion problem, but the other direction converting too much?

It is possible that you are overconverting T4 into T3. Up-regulated 5′-deiodinase activity is usually caused by elevated testosterone levels. Thyroid hormone resistance can also cause high levels of T3 and normal T4 levels, but this usually is characterized by a normal or elevated TSH.

All I know I had graves. I remember my TPO so high like 1500 and now it is down to 200 and now people tell me I might be developing Hashimoto’s Thyroiditis.

Your article was very helpful, and yes, I know I have fatty liver non Alcoholic and I changed my diet. It appears, I do not have graves for now or will I always have it. Anyway, I was tested for other immunes and clean and allergy clean except for dust mites, mold.

I want to know I started taking colostrum and I also take B panel that has good folic acid with the MTH in front and same with B12. I take cod liver oil, Vitamin D, B6 100mg,and Selenium.

How can I deceased my deodinase, or increase if I have too. What are cytokines or not make them inflamed. How can I correct them and I know diet is something that I am always working on and especially, our foods of today; which is also another subject and many issues that can be subject to thyroid.

The best method of affecting the deiodinases is by focusing on the factors I discussed in the post. In other words, make sure you aren’t selenium deficient, try to do a good job of managing your stress, improve the health of the liver and gut, be aware of any medications which can affect deiodinase activity, do things to reduce pro-inflammatory cytokines, etc. As for what pro-inflammatory cytokines are and how to lower them, I would read the following post I wrote in the past on cytokines:

Low T4 and/or low T3 are common with hypothyroid conditions, with Hashimoto’s Thyroiditis being the most common cause. While taking thyroid hormone medication might be necessary if both are low, addressing the cause of the problem is also important. I would recommend attending one of my free webinars on hypothyroidism and Hashimoto’s Thyroiditis for more information.

When I was taking Euthyrox (similar to Synthroid) my TSH was low, fT4 was at the high end of range and fT3 was always at the low end of range. I was feeling lousy. Now I’m on NDT (Thyroid S) and the latest test showed very low TSH (expected), fT4 at the bottom of range and fT3 at the top of range, which is great. I feel quite good.
So, should I worry about the low fT4 now, or this is ok?
Thank You

Since T3 is the active form of the hormone I’m more concerned when T3 is low. Plus, keep in mind that even if you are taking synthetic T4 it won’t increase T4 levels on the blood test, and so as long as the TSH and free T3 levels look good and you’re feeling good I wouldn’t be concerned about the low T4.

The first thing I would do is get an updated thyroid panel to also look at the thyroid hormone levels, and also test the TSI antibodies for Graves’ Disease. It is possible that the dosage of thyroid hormone medication you’re taking is too high. On the other hand, if you have elevated thyroid hormone levels and elevated TSI antibodies then this indicates you have Graves’ Disease.

I was diagnosed with Hypothyroidism almost 30 years ago and my Endocrinologist has told me that my thyroid gland is almost nonexistent. For this reason I am confused over treatment options when my only salvation is Synthroid. How can any natural product help my thyroid when it isn’t there? I need replacement therapy.
I would appreciate your insight on this important topic.
Thank-you.

I agree that you probably need to take thyroid hormone medication, as there is no natural substitute for thyroid hormone. However, there are better alternatives to Synthroid, as Tirosint doesn’t have all the chemicals that Synthroid has, although it is more expensive. And there is the option of taking natural thyroid hormone medication such as Armour or Nature-Throid.

I have low t4 to t3 conversion after being fine on t4 for 20 yrs. I took slow release t3 and cynomel but tried ndt since I still feel exhaused. I have Hashimotos and take all the supplement from STTM website as well as your suggestions. My temp is variable low 36.2-36.7 (was 35). I take numerous adrenal supplements as well. Any more suggestions for Hashi? I got my Thyr Abs from 3000 to 900. I am on a candida, gaps, fod map ,low estrogen diet and take numerous immune booster supplements.

It sounds like you’re doing some great things for your health, as you are eating well, avoiding the common allergens, doing things to heal the gut and improve the health of the adrenals, etc. I of course would make sure you are blocking out time to manage stress, minimize exposure to toxins, etc. If you haven’t attended one of my free webinars on hypothyroidism/Hashimoto’s I definitely would recommend doing so, as I go into greater detail about some of the things people with this condition need to do in order to greatly improve their health.

I was diagnosed with Hoshimoto’s and hypothyroidism in 2003 & I continue to get more symptoms & they have progressively become worse. (Had systemic candida from 1982-1995 when a live cell blood analysis showed tropical parasites in my blood which I believe was my trigger.) Changed from Armour Thyroid to NaturThroid 65mg 8/14. New Doctor (functional medicine) increased dosage to 97.5 mg in Oct. with labs that were fine. After labs 3/15 with TSH 0.10, Free T4 0.9, FreeT3 2.4, T3 Total 76, this new doctor increased the dosage again to 146.25. She also had me taking iodine since Oct. Fatigue even worse – have to nap every day. Very low energy level – have lost muscle. Hands not shaking but on the edge. Heart palpitations on couple of occasions. Heartburn back after getting rid of it several years ago but also feel strange sensations in neck area. Labs 5/15 TSH 0.03, Free T4 1.3, Free T3 2.3, T3 Total 56,TPO 14 reference range of <9 IU/ml . I have been doing a gut cleanse since 4/1/15. Lots of constipation, belching, gas, bloating. I am dairy, gluten, corn, soy, and sugar free. When stopped dairy in 2010 lost 12 lbs. Stopped gluten 2012 lost 3more lbs. Then started losing weight for no reason but previous Doctor & new Doctor not concerned. Now down to 103 lbs.& can see my rib cage and hip bones. Friends are concerned and so am I. Doctor feels I'm obsessing. I also feel I am hyperthyroid and may have adrenal issues. After changing her mind 4 times at my visit last week I am now taking 65 mg. NaturThroid. I think further testing needs to be done and I need to get to the bottom of the weight loss. Is it possible I have both hoshimotos and graves?

It sounds like you’re doing a lot of good things for your health, but based on what you mentioned in your post it might be time to look for a different doctor. It is possible to have the antibodies for both Hashimoto’s Thyroiditis and Graves’ Disease, although taking a higher dosage of thyroid hormone than is necessary can cause hyperthyroid symptoms (including weight loss). And of course there can be other reasons for the weight loss, and since your current doctor isn’t addressing any of your concerns it makes sense to get another opinion.

Having the same symptoms as you. I’m losing lots of weight. I also have Candia and other bacterial infections. I started looking at dr Jennifer Daniels videos and have started the turpentine protocol. It seems to be working fine. I’m keeping my fingers crossed.

The confusing part for me is you discuss a conversion problem of T4 to T3, but the proper test is FT4 and FT3. Should we be reading T4 and FT4 interchangeably in this article? If my labs show normal FT4 and low FT3, does that mean a conversion problem, even though I don’t know T4 and T3 levels? Thank you doctor.

Hi I am on Synthroid and cytomel but the cytomel makes me irritable and I have more hot flashes/ night sweats, blood pressure goes up, fluid retention, weight gain etc. I know you are supposed to add T3 meds with your T4 but it makes me feel worse ?

Nice one – its good to see someone beign fairly critical of taking Se willy-nilly. I used to do this and felt terrible. Then I read that selenium and iodine have a relationship, and that rather than taking large amounts, very small amounts are better – especially with Hashis’. Its easy to OD on Se. I am starting to wonder about liver function. My bilirubin levels are on the high side, as is cholesterol (on a healthy diet). I suspect low T3 and T4 was causing the high cholesterol problem but will need to check this. Juyst started acupuncture and chinese medicine- the acupunturist advised that I have a sluggish liver, which would explain continued energy issues even tho NDT has gotten T3 and T4 back to good levels. I can thoroughly recommend acupuncture as the sure-fire way to feel better from fatigue issues. Plus, an eastern perspective on healing can provide more insight into your own condition.

Hello, I went hyperthyroid around 2011 and then a couple of years later went Hypo and got diagnosed with Hashimotos. I was on Synthroid and then went to Armour and then to Nature throid. Seems like they work for a bit and then I get either hyperthyroid or high t4 low t3. They did suspect conversion problems. Right now Im functioning on no meds just vegan and taking vitamins, no sugar. Im tired though. I was wondering if liver flushes were ok to do with hypothyroid? I feel like my liver does get backed up and I start to feel crummy.

Hi Dr. Eric,
I have been hypo for over 30 yrs., on synthroid only for all of that time. About 8 months ago, my Dr. tested my TSH, FT4, and FT3. My results came back as FT4 18.5 (range 10.6-19.7) and FT3 3.73 (range 3.00-5.90), and TSH 1.59. I have been steadily gaining weight, fatigued, hot flashes, etc. I have also been in menopause for 6 years now, with my hot flashes only get worse, not better with time. My Dr. put me on T3 (Cytomel 25 mcg, and reduced my Synthroid to 125 mcg from 150 mcg). My most recent results are FT4 11.7, FT3 4.68, and TSH 0.02. My Dr. has been asking how I’ve been feeling, and I definitely don’t feel hyper at all, haven’t lost any weight, even though I don’t feel as fatigued. How would you interpret these results?
Thank you very much.
Petra

It sounds like the Cytomel might be working for you, although the last FT4 value is a little lower than I’d like to see. If you haven’t had your adrenals evaluated you might want to consider doing this, and having a healthy gut and liver is also important for optimal T4 to T3 conversion.

Although I can’t say with certainty that spironolactone doesn’t affect the conversion of T4 to T3, I did do some research on this after reading your comment, and I was unable to find any evidence of this.

I took T4 for 5 years with little effect. I have Hashimoto’s.
I added both T3 and Testosterone to my therapy over a year ago.
I now have muscle/joint stiffness, very slow recovery after exercise and exaggerated soreness time (sometimes 10 days post exercise). I get tendonitis easily and usually get it on both sides…achilles, golfer’s elbow, etc…Do you think that the T4/T3 combo could cause this? or Maybe the Testosterone replacement?
Starting a few days ago i’m using T3 only (still taking Testosterone as well) to see if that helps.

I’ve been tested for many things and so far everything all bloods are normal (C reactive protein, RA, etc…all negative).

Any advice or feedback is greatly welcomed…I’m so restricted in my activities now by pain, stiffness, and injury that I can only do swimming. Please Help. I was an athlete and always active.

I’m sorry that you’re experiencing muscle and joint stiffness. If this started shortly after taking T3 and testosterone then it’s possible that one of these is the culprit. It might not be the hormone itself, but perhaps one of the other ingredients. The only way to know for certain would be to ask your doctor to take a break from these and see if the muscle and joint stiffness subsides. I know you have been tested for many things, but if taking a break from the hormones doesn’t help then you might want to look into infections, including Lyme disease, although many people with this have migrating muscle and joint pain.

Thank you Dr. Eric,
I’m experimenting doing T3-only right now (with Testosterone replacement). If after a month or so I don’t start feeling better I will try T4-only for a while (with Testosterone replacement). If that doesn’t help I will go off of Testosterone for a couple of months, or longer? What do you think?

Also, I just read a few articles about how Hypothyroid changes your muscle fibers from fast twitch type II to slow twitch muscles. It causes slower muscle relaxation which I can imagine makes it much easier to get injured during aggressive exercise. I’ve been reading the L-Carnitine or Acetyl-L-Carnitine might be helpful. I want to fight this, but if I can’t exercise vigorously then I will lose….better to find a cure first.

Yeah, i tried slow jogging and restrained my calf or soleus. The only thing I seem to be able to do right now without garnering an injury is running/swimming in the pool. This is so frustrating.

Yeah, it’s nice to come across a Dr who is researching the problems and actually using the symptoms as guide (not just blood test results). I feel like I am very close to the answer to these muscle/tendon problems but, just don’t know exactly what is causing them yet. I need to do my due diligence doing my experiments until I can rule out enough causes and remedies to find something that works. I might cut out all my vitamins as well and just try T3-only and in a few weeks add L-Carnitine.

It could also be that people with Hypothyroid switch from Fast Twitch Type II to the Slow Twitch Type I muscles because they stop being active….so maybe it’s not the hypothyroidism but the lifestyle changes that accompany the pain and fatigue. I’m reading other articles that debunk the L-Carnitine preventing the muscle fiber changes. I’m unsure and still doing research.

My T3 levels are low and my TSH is high. I have TPO antibodies present and have diagnosed myself with Hashimotos disease. When I addressed the problem to my doctor she said she couldn’t do anything for me until my thyroid gland was burnt out. Then she would put me on medication for life. I have tried several other doctors and naturopaths and after a year of fighting I’m not sure much has changed. Should I go on a T3 medication?

If you have normal T4 levels and low T3 then this may be an indication to take synthetic T3. If both T4 and T3 are low then you might need to have your doctor increase the dosage of T4, although some people do take both synthetic T4 and T3. Another option to consider is to take a desiccated form of thyroid hormone, as this has both T4 and T3. While taking thyroid hormone replacement you want to address the cause of the problem, which it sounds like you tried doing by working with some naturopaths.

Mimi, a normal TSH and FT4 combined with a FT3 on the low side is a sign of a problem converting T4 to T3, which you know from reading this blog post. Suboptimal T3 levels is a concern since this is the active form of the hormone, and so while I wouldn’t get stressed out over this, I wouldn’t ignore these findings. Of course you can always try doing another thyroid panel in 4 to 6 weeks and see if the readings are similar before taking action.

Lately my tests have been good for T4, but TSH is still high. My doctor is clueless, wanted me to increase my thyroid med, it makes me feel worse when I do. I am stuck. Liver tests show normal, so do kidney, yet I have odd symptoms. Now am pre-diabetic. grrrrrr. Wish I could afford to work with you, but…. Thank you for providing the ongoing information. I appreciate it.

TSH 0.29
FT3 2.7
FT4 1.35 (direct)
Dr. Eric,
I have had a complete thyroidectomy due to cancer and I am currently on 60 Armour and 75 Levo. I am wondering how do I get my T3 levels up and do you have any other recommendations.
I am female 45 yrs old, 5’3, 170 pounds and watch what I eat and have been working out 5 times a week for about 3 months. I have lost a couple of pounds but I really need to lose weight. 3 days cardio, 2 days strength training. Thank you.
Laura Castro

Laura, as I discussed in the blog post, improving the health of your liver, gut, and adrenals can help with the conversion of T4 to T3, which in turn can lead to higher T3 levels. I would also recommend reading the following post: